Preparing the Paediatric Investigation Plan application

Abstract

In Europe, sponsors must possess a compliant Paediatric Investigation Plan (PIP) when applying for marketing approval of drugs. The core deliverable is the ‘scientific part of the application’ structured according to the EMA's PIP guideline. The PIP should summarize relevant background information on the disease and drug, and use this to justify a paediatric development programme that covers the entire paediatric population. Depending on the type of drug and the relevance of the disease to the paediatric population, specific quality, safety, and/or efficacy measures may be proposed for all or part of the population. If measures are considered inappropriate for all or part of the paediatric population, then a waiver may be proposed but must be justified. If the paediatric development programme cannot be completed before submission of the adult application, then a deferral of the paediatric measures may be proposed but again this must be justified. In any case, a detailed timetable has to be provided and adhered to for any all measures being proposed. The main challenges for medical writers when writing a PIP are application of the guidance to the drug and disease in hand, and obtaining the appropriate input from the project team.

Keywords:

• Paediatric Investigation Plan
• Waiver
• Deferral
• Paediatric measure
• Application

Pharmacokinetics series Children are not ‘small adults’

For many years the therapeutic drug dose in children was determined by simply making a proportional adjustment of the adult dose based on the weight of the child relative to the adult. The view that children are just ‘small adults’ has been debunked by a greater understanding of physiological and biochemical ontogeny and the pharmacological differences that can occur in children compared with adults. Developmental changes in the 4 main pharmacokinetic (PK) processes, absorption distribution, metabolism and elimination (ADME) have been noted. For example changes with age in the absorptive surface areas such as the gastrointestinal tract, skin and lungs can influence the bioavailability of a drug. Generally clearance mechanisms in infancy and early childhood are inefficient. The drug metabolising enzyme cytochrome P450 1A2 (CYP1A2) is absent in neonates therefore they are unable to metabolise caffeine to paraxanthine. Adult levels are only reached after 1 year of age. CYP2C9 (which accounts for approximately 20% of oxidative drug metabolism) activity increases from birth to 10 years of age whereupon it exceeds that of an adult, thereafter there is a decline to adult levels. Renal function as measured by glomerular filtration rate develops with age. Adult values are generally reached by 1 year of age. Genetic variants of ADME genes, different disease phenotypes, disease progression, and concomitant treatment all contribute to this variation.

The paediatric population is far from homogenous, variability is potentially larger than that observed in the adult population. Based on organ maturation, body weight and body composition children can be classified into at least 4 different population categories; neonates (birth to 28 days), infants (28 days – 23 months), children (2–11) and adolescents (12 to 16/18 years old)¹. The challenge for the drug developer is to understand the heterogeneity and how this affects the pharmacokinetic/pharmacodynamic relationship and ultimately the therapeutic dose; is it sufficiently different to that found in adults to warrant a dose adjustment?

Presently around 70% of the medicines given to the paediatric population and 93% of the medicines given to critically ill neonates remain unlicensed or are used off-label². The regulatory authorities have taken steps to address this imbalance. The EMA state that for all new chemical entities innovators must consider a paediatric investigational plan (PIP). In some instances a waiver will be granted where the disease is not present in children, for example Parkinson's' disease. In all other cases a series of studies are required to investigate the quality, safety and efficacy of the drug in children to allow choice of the appropriate dosing regimens.

Estimating PK in children can be challenging, the mantra oft said is ‘the need to do more with less’. Blood sampling for drug measurement is less extensive compared with adults (it's a volume issue!) and subjects tend to be fewer. This scenario lends itself to the use of population PK methodology³. Here data from all patients are analysed together and a mean set of population PK parameters (generally clearance and apparent volume of distribution) are estimated. The variability around these parameters can then be investigated in terms of the different age groups etc, within the paediatric population. A caveat with this technique is that to fully understand dose adjustment in each of these cohorts a sufficient number of patients needs to be investigated in each of the sub-groups of interest.

Understanding drug behaviour in children has great societal value. For new medicines it will result in the early licensing of innovative products for paediatric use. For existing drugs, the development of child appropriate formulations coupled with a greater understanding of the PK/PD relationships in children will increase the armamentarium of safe and effective medicines available to treat childhood disease.

Graham Blakey

Clinical Pharmacology and Pharmacokinetics Consultant

GBPK Consulting Ltd

[email protected]

http://www.gbpkconsulting.co.uk

Additional information

Notes on contributors

Douglas Fiebig

Douglas Fiebig started his career as a medical writer at Hoechst in 1996, after receiving his PhD in environmental microbiology and spending several years in academic research. After the company went through several mergers, culminating in the formation of Aventis, Douglas and two colleagues co-founded Trilogy Writing & Consulting in 2002. The focus of his work has been writing for regulatory submissions in all major pharmaceutical markets. Douglas has been involved in preparing Paediatric Investigation Plans (PIPs) since they became mandatory in 2007. He regularly runs workshops on the practicalities of writing PIPs for EMWA and other organizations, and currently serves in the EMWA Professional Development Committee.